title: Autism traits in the RASopathies.
abstract: BACKGROUND
  Mutations in Ras/mitogen-activated protein kinase (Ras/MAPK) pathway genes lead to a class of disorders known as RASopathies, including neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Costello syndrome (CS), and cardio-facio-cutaneous syndrome (CFC). Previous work has suggested potential genetic and phenotypic overlap between dysregulation of Ras/MAPK signalling and autism spectrum disorders (ASD). Although the literature offers conflicting evidence for association of NF1 and autism, there has been no systematic evaluation of autism traits in the RASopathies as a class to support a role for germline Ras/MAPK activation in ASDs.
  
  
  METHODS
  We examined the association of autism traits with NF1, NS, CS and CFC, comparing affected probands with unaffected sibling controls and subjects with idiopathic ASDs using the qualitative Social Communication Questionnaire (SCQ) and the quantitative Social Responsiveness Scale (SRS).
  
  
  RESULTS
  Each of the four major RASopathies showed evidence for increased qualitative and quantitative autism traits compared with sibling controls. Further, each RASopathy exhibited a distinct distribution of quantitative social impairment. Levels of social responsiveness show some evidence of correlation between sibling pairs, and autism-like impairment showed a male bias similar to idiopathic ASDs.
  
  
  CONCLUSIONS
  Higher prevalence and severity of autism traits in RASopathies compared to unaffected siblings suggests that dysregulation of Ras/MAPK signalling during development may be implicated in ASD risk. Evidence for sex bias and potential sibling correlation suggests that autism traits in the RASopathies share characteristics with autism traits in the general population and clinical ASD population and can shed light on idiopathic ASDs.
authors.affiliation: Department of Psychiatry, University of California San Francisco, San Francisco, California, USA.
authors.forename: Brigid
authors.initials: B
authors.lastname: Adviento
authors.forename: Iris L
authors.initials: IL
authors.lastname: Corbin
authors.forename: Felicia
authors.initials: F
authors.lastname: Widjaja
authors.forename: Guillaume
authors.initials: G
authors.lastname: Desachy
authors.forename: Nicole
authors.initials: N
authors.lastname: Enrique
authors.forename: Tena
authors.initials: T
authors.lastname: Rosser
authors.forename: Susan
authors.initials: S
authors.lastname: Risi
authors.forename: Elysa J
authors.initials: EJ
authors.lastname: Marco
authors.forename: Robert L
authors.initials: RL
authors.lastname: Hendren
authors.forename: Carrie E
authors.initials: CE
authors.lastname: Bearden
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Rauen
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Weiss
mesh_terms: D000293:Adolescent; D000328:Adult; D001321:Autistic Disorder / Q000175:diagnosis / Q000235:genetics*; D002648:Child; D056685:Costello Syndrome / Q000175:diagnosis / Q000235:genetics*; D003937:Diagnosis, Differential; D004476:Ectodermal Dysplasia / Q000175:diagnosis / Q000235:genetics*; D019066:Facies; D005183:Failure to Thrive / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D006330:Heart Defects, Congenital / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D009483:Neuropsychological Tests; D009634:Noonan Syndrome / Q000175:diagnosis / Q000235:genetics*; D063868:Patient Outcome Assessment; D010641:Phenotype; D015995:Prevalence; D019655:Quantitative Trait, Heritable; D012737:Sex Factors; D035781:Siblings; D015398:Signal Transduction; D011795:Surveys and Questionnaires; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins
keywords: Autism; Costello Syndrome; Cranio-Facio-Cutaneous Syndrome; Neurofibromatosis Type 1; Noonan Syndrome